Stable topical retinoid compositions

ABSTRACT

Compositions for topical application to the skin are provided, which compositions comprise a retinoid in an aqueous vehicle, and further contain at least one non-ionic surfactant, wherein the non-ionic surfactant is the crystallization-preventing and stabilizing agent for said retinoid and is selected from the group consisting of polyoxyethylene mono fatty alcohol ethers, polyoxyethylene glyceryl fatty acid triesters and ethyleneoxide/propyleneoxide block copolymers.

The present invention relates to aqueous pharmaceutical and cosmeticcompositions, comprising a retinoid, for topical application to theskin.

BACKGROUND OF THE INVENTION

Topical compositions, comprising a retinoid in an aqueous vehicle, areknown.

Vitamin A acid or retinoic acid, IUPAC name3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoicacid, has been used topically for the treatment of acne vulgaris andrecently also for the treatment of ageing skin. The naturally occurringform is the all-trans compound or tretinoin, but cis compounds are alsoknown. The 13-cis compound or isotretinoin is also used as a keratolyticagent. Both isomers and derivatives thereof, such as salts, esters andamides, and structural analogues, such as etretinate, belong to thegroup of the retinoids.

WO 90/14833 (Bazzano) discloses a stable, aqueous composition fortopical application to the skin, comprising a retinoid. Said compositionmay also comprise 0.1 to 20 wt % of a solubilising agent (ethanol) and asurfactant, the last mentioned ingredient being added in order to havethe dual benefit of helping to maintain the active ingredient in uniformsuspension in the formulation, while enhancing the bioavailability ofthe active ingredient.

However, the stability of the compositions is still rather limited:table II at page 17 mentions the percentage decomposition of tretinoinin 7 formulations, said percentage ranging from 3 to 13% after 10months' storage. Furthermore, all examples show compositions comprisinga substantial amount of the solubilising agent ethanol. It, thus, is tobe expected that said compositions, due to the presence of saidsolubilising agent, still cause irritation and inflammation of the skin.

EP-A-393904 (Maxam) discloses a water-based, alcohol-, oil- and fat-freeformulation comprising tretinoin in a not completely solvated form, agelling agent and a proteinaceous material for stabilising the gellingagent. The formulation may further comprise one or more of anantioxidant, a preservative and glycerin. A surfactant, the choice ofwhich does not seem to be critical, may also be incorporated in theformulation to allow good dispersion of the active ingredient and toenhance skin penetration. The compositions are said to be physically andchemically stable. However, it is well-known that proteinaceousmaterials, such as proteins, polypeptides, peptides, amino acids andmucopolysaccharides as mentioned in the specification, are prone tomicrobial attack and/or chemical degradation, especially in aqueousvehicles. Therefore, the stabilising effect exerted by said materialswill be limited.

Reference is made further to U.S. Pat. Nos. 4,022,913 and 4,532,133which both disclose compositions comprising vitamin-A alcohol esters foruses like high potency vitamin preparations and additives in animalfeed.

The compositions of the present invention comprise compounds derivedfrom vitamin-A acid which are not the subject of above references.

Retinoids are insoluble or at most very slightly soluble in water, butreadily soluble in e.g. ethanol. Therefore retinoid containingpreparations have been most effectively applied using an alcoholcontaining solvent system, which causes an uncomfortable burningsensation by itself. Said sensation is amplified when applied to skinwhich was previously or is simultaneously treated with retinoic acid.Cream formulations were found to be generally more acceptable topatients, but they were found to have other disadvantages, such as areduced clinical effectiveness as compared with alcoholic compositionscontaining the same amount of retinoic acid and sometimes a comedogeniceffect due to fats and oils, used in the formulations. Aqueous retinoicacid preparations containing no alcohol and no fats have not shown to beclinically very effective, due to the fact that the active ingredient isnot dissolved and, thus, not available for exerting the desired effect.

There, thus, exists a need for a composition comprising a retinoid,which composition:

is chemically and physically stable;

does not contain alcohol; and

is clinically at least as effective as a prior art composition,containing said retinoid in an alcoholic vehicle.

SUMMARY OF THE INVENTION

The present invention provides a composition, comprising a retinoid inan aqueous vehicle, containing at least one crystallisation preventingand stabilising agent, chosen from the group of non-ionic surfactants.It is another object of the present invention to provide a method forthe preparation of aqueous compositions comprising a retinoid by the useof at least one crystallisation preventing and stabilising agent; saidagent being chosen from the group of non-ionic surfactants.

DETAILED DESCRIPTION OF THE INVENTION

Non-ionic surfactants are known per se and expendiently the compositionaccording to the invention comprises a non-ionic surfactant chosen froma polyoxyalkylene compound, a polyoxyalkylene polymer, a polyoxyalkyleneblock copolymer or a mixture of two or more of such substances.Generally the alkylene moiety of said substances comprises from 2 to 5carbon atoms, preferably 3 or 4 carbon atoms. In particular abovenon-ionic surfactants are represented by polyoxyethylene fatty alcoholethers, polyoxyethylene glyceryl fatty acid triesters and ethyleneoxyde-propylene oxyde block copolymers.

Very suitable representatives of above non-ionic surfactants arepolyoxyethylene (4) monolaurylether, polyoxyethylene (25)glycerintrioleate and a liquid ethyleneoxyde / propylene-oxyde blockcopolymer containing 40% of ethylene oxyde and 60% of propylene oxydeand having a molecular weight of 2.000-3.000 (SYNPERONIC PE/L44®)respectively.

In a further advantageous embodiment a composition according to theinvention comprises a further non-ionic surfactant chosen from the groupof polyoxyethylene glycerin fatty acid monoesters such aspolyoxyethylene (15) glycerin monolaurate.

It has been found that the addition of at least one crystallisationpreventing and stabilising agent to compositions comprising a retinoidin an aqueous vehicle having a pH of between 3 and 7, surprisingly leadsto an improvement of the chemical stability of the active ingredient.This has in particular been demonstrated for compositions, comprising aretinoid and a polyoxyethylene monoether in an aqueous vehicle, bothupon storage at elevated temperatures during several months and uponstorage at ambient conditions during at least 18 months.

On microscopic evaluation of the compositions according to the inventionno crystals of the active ingredient have been observed, also not afterstorage for more than one year at room temperature. In order to increasethe availability of the active ingredient and, thus, its clinicalefficacy, an organic solvent, such as a monohydric C₁ -C₃ -alkanol andespecially ethanol and/or isopropylalcohol, had to be incorporated inprior art compositions comprising retinoic acid. In the compositionsaccording to the present invention no substantial amounts of suchorganic solvent are needed, although it may be present in an amount ofup to 5 wt %, preferably up to 1 wt % and more preferably in an amountof 0-0.1 wt %. An advantage of the compositions according to the presentinvention is that the extreme drying effect on the skin, due to the useof relatively high amounts of organic solvents in prior artcompositions, has been avoided. Furthermore, water-based compositions donot provide any problem relating to environmental and safety aspects.

The compositions according to the present invention comprise a topicallyeffective amount of a retinoid and can be successfully used for thetopical treatment of acne vulgaris and of ageing skin. However, othertopically effective drugs, which may enhance the therapeutic effect ofthe retinoid, may be incorporated without any negative effect on thestability or clinical efficacy. Examples thereof are corticosteroids andantibiotics. Preferably, water soluble antibiotics such as clindamycinphosphate or the hydrochloric acid addition salt thereof are used. Thecombination products of retinoic acid and clindamycin phosphateaccording to the invention have proved to be in particular suitable forthe mixed forms of acne vulgaris: comedonic acne with mild to moderateinflammation. For this indication usually either a topicalantibiotic-containing preparation or a topical tretinoin-containingpreparation is prescribed. Once daily application of the combinationproducts according to the invention suffices.

The concentration of a retinoid in the composition may range from 0.001to 0.5 wt %, preferably from 0.01 to 0.1 wt % and most preferably from0.025 to 0.05 wt %.

As indicated earlier an advantageous group of non-ionic surfactants isformed by the polyoxyethylene monoethers such as polyoxyethylene (4)monolauryl ether. The latter product is also known under the CTFA-nameLaureth-4 and available on the market under the Trade Names BRIJ 30;VOLPO L4 and SIMULSOL P4 .

A further advantageous group of non-ionic surfactants is constituted bythe polyoxyethylene glyceryl fatty acid tri esters such aspolyoxyethylene (25) glyceryltrioleate. The latter product is on themarket available under the trade name TAGAT TO.

Another advantageous group of non-ionic surfactants is formed by theethylene oxyde / propyleneoxyde block copolymers; an example of thelatter product is SYNPERONIC PE/L44.

Above products give, when incorporated in a composition according to theinvention, good results in terms of stability and applicability.

Further improvements are found when in addition to the non-ionicsurfactants referred to a product chosen from the group ofpolyoxyethylene glycerin fatty acid monoesters is included. A typicalrepresentative thereof is polyoxyethylene (15) glycerin monolauratewhich is available under the trade name Glycerox L15®.

The amount of the non-ionic surfactants to be added to the compositionsdepends on the amount and on the type of active ingredient(s) used, butin general ranges from 0.5 to 20 wt %, preferably from 1 to 10 wt % andmore preferably from 2-5 wt %. If a combination of polyoxyethylenemonoether and a polyoxyethylene glycerin monoester is used the molecularratio of these compounds is between 10:1 and 1:1 (polyoxyethylenemonoether:polyoxyethylene-glycerin monoester) and, if the combination oflaureth-4 and polyoxyethylene-(15)-glycerol monolaurate is selected,preferably about 2.5. However, it is also possible to use a mixture ofrepresentatives from each group of non-ionics.

The viscosity of the aqueous vehicle may be increased by the addition ofviscosity enhancers well-known in the art, viz. cellulose-derivatives,such as hydroxypropyl cellulose, and polyacrylic acids, such as thoseavailable under the registered trademark Carbopol.

The pH of the compositions is preferably adjusted by the addition of aphysiologically acceptable buffering agent to a pH of between 3 and 7,but preferably of between 4.0 and 5.5.

As the retinoid is susceptible to oxidation and resulting decompositionin an aqueous medium, the compositions of the present inventionoptionally also contain an effective amount of one or more anti-oxidantsin a suitable concentration relative to the active ingredient, such asfrom about 0.01 to 4% by weight of the composition. Due to theabove-mentioned combination of surfactants, the effective concentrationof the anti-oxidant(s) in the compositions of the present invention maybe reduced as compared to prior art compositions comprising retinoicacid.

The compositions may contain up to about 10% of an emollient oranti-irritant as an additional help in relieving any drying effects onthe skin which is an intrinsic property of the active ingredient.Examples of said emollients are C₁₂ -C₂₂ fatty alcohols and fatty acidesters, silicone oils and vegetable oils. Examples of anti-irritants arenatural moisturizing factor, humectants, etc..

The compositions of the present invention may further comprise otherappropriate excipients, such as sequestrants, buffers and preservatives.

The compositions are preferably prepared according to methods as knownin the art for the preparation of compositions comprising compoundswhich may be readily oxidized in the presence of light and/or oxygen.Due to the above-mentioned combination of surfactants the totalexclusion of oxygen during the preparation of the compositions of thepresent invention may not be required.

In a clinical pilot study an aqueous composition according to thepresent invention has proved to be at least as effective as acommercially available prior art composition, comprising retinoic acidin an alcoholic vehicle.

All publications and patent applications cited in this specification areherein incorporated by reference as if each publication or patentapplication were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity andunderstanding, it will be readily apparent to those of ordinary skill inthe art in the light of the teachings of this invention that certainchanges and modifications may be made thereto without departing from thespirit and scope of the appended claims.

The following examples will illustrate the invention; all percentagesare in weight unless otherwise indicated.

EXAMPLES Example

    ______________________________________                                        retinoic acid     0.025%                                                      disodium edetate  0.10%                                                       butylhydroxytoluene                                                                             0.02%                                                       CARBOPOL ® 980                                                                              1.0%                                                        laureth-4         2.0%                                                        tromethamine      0.75%                                                       citric acid monohydrate                                                                         0.15%                                                       propyleneglycol   7.5%                                                        methylhydroxybenzoate                                                                           0.1%                                                        water till        100.0%                                                      ______________________________________                                    

I. Carbopol was added to a mixture of propyleneglycol and water.

II. Laureth-4 was heated until 35°-40° C., whereafterbutyl-hydroxytoluene, retinoic acid and methylhydroxybenzoate wereadded. The mixture was stirred until complete dissolution of thecomponents was achieved, excluding oxygen, protected against theinfluence of light.

III. Citric acid monohydrate and tromethamine were dissolved in waterunder stirring and heating until 50°-60° C.

Whilst stirring phase II was first added to phase I, and thereafterphase III was added, protected against light at a temperature of 50°-60°C. The whole was put under vacuum, stirred, further put under vacuum andsubsequently cooled till the temperature dropped below 30° C. Nitrogenwas added and the product was removed from the ointment mixer.

Example 2

    ______________________________________                                        retinoic acid     0.025%                                                      clindamycin phosphate                                                                           1.20%                                                       disodium edetate  0.10%                                                       butylhydroxytoluene                                                                             0.02%                                                       CARBOPOL ® 980                                                                              1.0%                                                        laureth-4         4.0%                                                        tromethamine      0.75%                                                       citric acid monohydrate                                                                         0.15%                                                       propyleneglycol   7.5%                                                        methylhydroxybenzoate                                                                           0.1%                                                        water till        100.0%                                                      ______________________________________                                    

The gel was prepared according to the manufacturing method of example 1;clindamycin phosphate was dissolved in water together with citric acidmonohydrate and tromethamine.

Example 3

Example 2 was repeated but now instead of 4% Laureth 4 a mixture of 2%Laureth 4 (polyoxyethylene (4) monolauryl-ether) and 2% GLYCEROX L15(polyoxyethylene (15) glycerinmono-laurate) was used.

An equally good product, in terms of stability and applicability, wasobtained.

Example 4

Example2 was repeated but instead of 4% Laureth-4 4% of eitherSYNPERONIC PE/L44 or TAGAT TO was used. An equally good product, interms of stability and applicability, was obtained.

Example 5

A double-blind, randomized, multi-center pilot study in 40 patients withmoderate to severe acne vulgaris, grade 3 or higher on the scoring scaleof Cook was performed in order to compare the efficacy of a prior artcomposition, comprising 0.025 wt % retinoic acid in an alcoholic gelvehicle, and a composition according to the present invention (theaqueous gel of example 2).

The medication was applied once daily at night on the acne lesions for aperiod of 12 weeks.

Both treatment groups responded to the therapy. The patients treatedwith the composition of example 2 had a more rapid response and thenumber of inflamed lesions after 12 weeks was significantly lower thanthe patients treated with the alcoholic retinoic acid gel. The treatmentgroups showed to be comparable with respect to the non-inflamed lesions,although a numerical difference in favour of the composition accordingto the present invention could be assessed.

We claim:
 1. A composition for topical application to the skincomprising a retinoid in an aqueous vehicle said aqueous vehicle furthercomprising up to 5 wt % of an organic solvent, and at least onenon-ionic surfactant wherein the aqueous vehicle has a pH of between 3and 7 and the non-ionic surfactant is a crystallization preventing andstabilizing agent for said retinoid and is selected from the groupconsisting ofa) polyoxyethylene mono fatty alcohol ethers, b)polyoxyethylene glyceryl fatty acid triesters, and c) ethyleneoxide/proclaim oxide block copolymers.
 2. A composition according toclaim 1 wherein the non-ionic surfactant is selected from the groupconsisting ofa) polyoxyethylene (4) monolaurylether, b) polyoxyethylene(25) glyceryltrioleate, and c) SYNPERONIC PE/L44, a liquidethyleneoxide/propyleneoxide block copolymer containing 40% ofethyleneoxide and 60% of propyleneoxide and having a molecular weight of2.000-3.000 respectively.
 3. A composition according to claim 1comprising a further non-ionic surfactant chosen from the group ofpolyoxyethylene glycerin fatty acid monoesters.
 4. Composition accordingto claim 4 wherein the polyoxyethylene glycerin fatty acid monoester ispolyoxyethylene (15) glycerin monolaurate.
 5. A composition according toclaim 1 wherein 0-0.1 wt % of the organic solvent is present. 6.Composition according to claim 5, wherein the organic solvent is amonohydric C₁ -C₃ alkanol.
 7. A composition according to claim 1 whereinthe composition contains an antibiotic.
 8. Composition according toclaim 7 wherein the antibiotic is clindamycin or a derivative thereof.